New Paradigm Is Shaping Up for High-Risk Smoldering Myeloma

Andrew Smith

Published: Tuesday, Feb 12, 2019

Elisabet E. Manasanch, MD

The nature of smoldering multiple myeloma (SMM) is such that it can develop very rapidly into multiple myeloma (MM) or take years. However, since the disease was first identified almost 40 years ago by Robert Kyle, MD, and Philip Greipp, MD, observation has remained the standard of care.1 During that time, more than a dozen new treatments have boosted survival times for individuals with MM. Now, researchers have begun trials to investigate whether any of those MM treatments might improve on observation for patients with SMM who are at the highest risk of progression.

There have been many discussions whether to treat with established regimens for MM or attempt novel agents that may produce less toxicity. Both options are currently under investigation in numerous trials, said Elisabet E. Manasanch, MD, an assistant professor in the Department of Leukemia and Myeloma at The University of Texas MD Anderson Cancer Center in Houston. The use of established MM therapies has been very successful and results in a large proportion of patients with deep responses. “However, this is at the expense of some toxicity, and long-term follow-up data are lacking,” she said. The alternative approach consists of testing other better-tolerated regimens, such as immunotherapeutics, as single agents, combination elements, or vaccines.

High-dose chemotherapy has the potential to reduce SMM to undetectably low levels, but its use comes with a high risk of toxicity and the potential for secondary cancers. “These drawbacks are particularly serious in patients who have no symptoms and may not develop any symptoms for years to come, which is why there’s also a lot of interest in testing other types of combinations that might prove a less traumatic way to improve outcomes,” Manasanch said.

SMM was originally defined to identify a group of 6 patients with 10% or more plasma cells (PCs) in the bone marrow and no organ damage at diagnosis who did not develop organ dysfunction related to MM for ≥5 years. It is now clinically defined as a clonal PC disorder that is diagnosed when patients have ≥10% to 59% clonal PCs in the bone marrow or elevated levels of monoclonal protein (M-protein; ≥3 g/dL in serum or ≥500 mg/24 h in urine) or both, but an involved/ uninvolved free light chain ratio (FLCr) <100, no end-organ damage, and no more than 1 focal bone lesion.2 The asymptomatic nature of the condition means that many cases go undiagnosed, so researchers have struggled to estimate the overall incidence.3

Whereas SMM may progress to MM rapidly or not at all, investigators have developed several systems for differentiating patients with higher and lower progression risks. The Mayo Clinic model, for example, uses M-protein (≥3 g/dL), bone marrow PC% (BMPC; ≥10%), and FLCr ≥8 to sort patients into 3 risk categories. Patients who reach or exceed 1 of those thresholds have the lowest risk of progression, while patients who reach or exceed all 3 of those thresholds have the highest risk of progression: 76% of them develop MM in 5 years.4 More recently, the International Myeloma Working Group has developed a proposed stratification model based on a slightly different set of biomarkers: BMPC >20%; M-protein > 2 g/dL; and FLCr > 20. Patients are classified based on 1, 2, or 3 of these biomarkers into low- to high-risk categories (Figure).4

At least 1 trial for patients with high-risk SMM has demonstrated an overall survival (OS) benefit for early immunotherapy intervention versus observation alone. The Spanish Myeloma Group randomized 119 patients with high-risk SMM to observation or a combination of lenalidomide (Revlimid) and low-dose dexamethasone. In the treatment arm, a partial response (PR) or better of 90% and a complete response (CR) of 26% were achieved during the trial’s maintenance phase. The median time to progression was 21 months in the observation group versus not reached among treated patients (P <.001). OS was not reached in either group, and the proportion of patients alive at 3 years after study enrollment was 94% versus 80% in the treatment and observation groups, respectively (P = .03).5